This invention is concerned with a dissolution cell and method for determining the in-vitro release of a drug in suitable form.
After rectal administration of a suppository, the in-vivo release of the drug contained in the base is sometimes irregular and incomplete which, among other reasons, is due to poor release of the drug from the suppository. The drug release characteristics, in general, are greatly influenced by the type of base and the excipients used in the suppository formulations. The dissolution property of the drug itself can also be an important factor in determining the in-vivo and/or in-vitro release of drug from the suppository.
One basic problem in testing for drug release from a suppository is that the suppository softens, deforms, melts, or disintegrates during the test, exposing a variable interfacial area to the dissolution medium. Because the release rate is dependent on this interfacial area, the variability of this factor leads to poor test reproducibility.
Many investigators have tried a number of approaches to study the correlation between in-vitro and in-vivo release of a drug from suppositories. The methods so far available for in-vitro dissolution testing, in general, are lacking in universal acceptance and reproducibility and are difficult to perform. As a result, no single method or device has emerged as a standard procedure for studying pharmaceutical availability of a drug administered in suppository form. Furthermore, no officially recognized dissolution test for suppositories has been mandated yet by any regulatory agencies.
The methods available for studying the in-vitro release rate of suppositories can be classified in terms of five general types.
The first type consists of placing a suppository in a beaker containing a dissolution medium, e.g. phosphate buffered solution, and supporting the suppository with wire or pins at both ends. A stirrer is immersed in the beaker to allow the dissolution medium to circulate about the suppository. Release of drug is determined by taking up samples of the dissolution medium and analyzing their content spectrophotometrically. See for example Biopharmaceutics of Aminophylline Suppositories, C. J. de Blaey and J. J. Rutten--Kingma Pharm. Acta. Helv. 52. Nr. 1/2 (1977). This method is not effective since the suppository floats on top of the dissolution medium and dissolution is not uniform.
The second type utilizes the USP dissolution wire basket for holding the suppository. The USP dissolution wire basket consists of a cylindrical container made primarily of wire mesh and open at the end for insertion of the suppository. It is suspended in the dissolution medium and rotated. The medium flows through the mesh material and contacts the suppository. Release of drug is determined spectrophotometrically. The disadvantage of this method is that the mesh material of the basket becomes clogged with the suppository composition base material, e.g. wax, which affects the release rate measurement.
The third type employs a membrane in a diffusion cell, wherein a receiver compartment is separated from a donor compartment by a membrane across which the released drug migrates. The donor compartment separated by the membrane is equipped with a port for introducing a drug sample to be tested for release rate, e.g. a suppository and a stirrer. The receiver compartment is also equipped with a stirrer and a sample port for removal of released sample. Both compartments contain a dissolution medium, e.g. phosphate buffer having a pH approaching that of the rectal area. See for example E. R. Garrett and P. B. Chemburkar, J. Pharm. Sci. 57(6), 944 1968. Membranes have been considered more suitable in release rate studies on the assumption that the interfacial area of the suppository would be controlled as the softened mass of suppository would spread over the entire membrane. However, the introduction of an additional physical process, i.e. membrane transport, can complicate matters and may mask the real release characteristics for certain drug-suppository base combinations. Another disadvantage of this procedure is that it employs compartments which are only 9 ml. in volume. Thus when samples are taken for measurement only a limited liquid volume remains for further sample removal.
In the fourth method for studying release rate of suppository, the suppository is placed in a dialysis tube, its both ends tied and then placed in the dissolution medium. Samples of the dissolution medium are taken periodically to determine the amount released. See J. J. Tukker and C. J. de Blaey Acta. Pharma. Tech. 29(2) 131 (1983).
In the fifth method a continuous flow system instrumental set up is employed. The apparatus consists of a glass bead-bed containing the suppository. A continuous flow of liquid is passed through the bead-bed at a constant rate. Direct contact of the suppository is maintained with the dissolution medium confining the suppository within the beads. See for example T. J. Roseman, et al, J. Pharm. Sci. Vol. 70, No. 6, June 1981.
The present invention, on the other hand, provides a simple and effective dissolution cell for determining drug release in-vitro. This cell allows the suppository to disperse in the dissolution medium and provides reproducible release rate data.
Experiments using this device gave good reproducibility and thus helped find in-vitro release rate and rank order for various formulations. Because the cell allows simple, quick and reproducible results, it can be applied to study the effect of formulation differences on drug release for suppository categories of products.